BIOLOGY OF REPRODUCTION 83, 325331 (2010) Published online before print 5 May 2010. DOI 10.1095/biolreprod.110.

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Maternal Undernutrition Influences Placental-Fetal Development1
Louiza Belkacemi,2,3 D. Michael Nelson,4 Mina Desai,3 and Michael G. Ross3
Department of Obstetrics and Gynecology,3 Harbor-UCLA Medical Center, Los Angeles Biomedical Research Institute at Harbor-UCLA, and David Geffen School of Medicine at UCLA, Torrance, California Department of Obstetrics and Gynecology,4 Washington University School of Medicine, St. Louis, Missouri ABSTRACT
Maternal nutrition during pregnancy has a pivotal role in the regulation of placental-fetal development and thereby affects the lifelong health and productivity of offspring. Suboptimal maternal nutrition yields low birth weight, with substantial effect on the short-term morbidity of the newborn. The placenta is the organ through which gases, nutrients, and wastes are exchanged between the maternal-fetal circulations. The size, morphology, and nutrient transfer capacity of the placenta determine the prenatal growth trajectory of the fetus to influence birth weight. Transplacental exchange depends on uterine, placental, and umbilical blood flow. Most important, maternal nutrition influences factors associated not only with placental homeostasis but also with optimal fetal development. This review associates fetal growth with maternal nutrition during pregnancy, placental growth and vascular development, and placental nutrient transport. fetus, IUGR, placenta, programming, undernutrition

transporter abundance. During normal pregnancy, the placenta undergoes a variety of physiological changes, regulated by angiogenic factors, hormones, and nutrient-related genes, to maximize efficiency for an ever-increasing demand for nutrients. Perturbations in the maternal environment following MUN may adversely alter these changes. This review discusses the influence of MUN during pregnancy on placental development and nutrient transfer. It also describes the subsequent effects on fetal development. MUN AND PLACENTAL DEVELOPMENT The placenta of mammals is a highly efficient multifunctional organ that integrates signals from both mother and fetus to match fetal demand with the maternal substrate supply of nutrients and gases, while ensuring that fetal waste products are transferred back to the mother. Altered placental structure and function (reflected by weight, morphology, vascular development, and transport function for amino acids, glucose, and fatty acids) may contribute to altered nutrient supply. Effects on Placental Weight Placental weight is correlated with dietary intake in mammalian pregnancies. Although the effect of global MUN on placental weight is unequivocal, the timing, duration, and etiology of nutritional restriction can each differently affect placental mass. A frequently cited example of this premise is the effect of timing and duration of limited nutrient intake during the Dutch Famine of 19441945 [9]. Women subjected to starvation in their third trimester of pregnancy had light placentas and newborns with low birth weight but an unaltered placental weight:birth weight ratio compared with nonstarved women. In contrast, exposure to famine only during the first trimester of pregnancy enhanced placental weight at delivery, although without any effect on newborn weight compared with control women. These results suggest that human placental adaptation in early pregnancy can overcome environmental stressors so that fetal nutrition is maintained in late gestation. Similar to humans, global MUN during early to mid pregnancy in sheep increased the placental weight:fetal weight ratio by enhancing placental weight at term without altering fetal weight [10]. Conversely, a 50% MUN during the second half of rat pregnancy yielded a decrease in the placental weight:fetal weight ratio [11], implying that MUN irreversibly affects placental weight when nutrient deprivation coincides with the time when fetal nutrient demand is maximal. An important question is whether global MUN or deprivation of a selected nutrient component is the insult that 325

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INTRODUCTION An optimal maternal nutrient supply has a critical role in placental-fetal growth and development. Maternal suboptimal nutrition during pregnancy results in intrauterine growth restriction (IUGR) and newborns with low birth weight. Intrauterine growth restriction is associated with increased perinatal morbidity and mortality, and newborns with low birth weight have increased risk for development of adult metabolic syndrome [1, 2]. Adverse effects of maternal undernutrition (MUN) have generally focused on the reduced maternal nutrient supply to the fetus. Few studies [38] highlight the crucial role of the placenta on the ensuing phenotype. The placenta forms the interface between the maternal-fetal circulations and as such is critical for fetal nutrition and oxygenation. In turn, the placental supply of nutrients to the fetus depends on its size, morphology, blood supply, and
Supported by a Los Angeles Biomedical Research Institute Seed Grant. Correspondence: Louiza Belkacemi, Department of Obstetrics and Gynecology, Harbor-UCLA Medical Center, Los Angeles Biomedical Research Institute at Harbor-UCLA, and David Geffen School of Medicine at UCLA, Torrance, CA 90502. FAX: 310 222 4131; e-mail: lbelkacemi@obgyn.humc.edu
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Received: 2 March 2010. First decision: 28 March 2010. Accepted: 27 April 2010. 2010 by the Society for the Study of Reproduction, Inc. eISSN: 1529-7268 http://www.biolreprod.org ISSN: 0006-3363

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induces the change in growth trajectories of the placenta and fetus. Notably, selective protein deprivation is a key factor in the dietary alteration of placental weight:fetal weight ratios. Protein restriction with 9% vs. 18% casein in the diet throughout pregnancy in the rat yielded heavier placentas and reduced fetal growth in late gestation [12]. The placental overgrowth compensates for the reduced protein availability in early gestation to maintain normal fetal weight in earlier gestation, but such compensation is insufficient to maintain fetal growth near parturition. Normal or even excess fetal growth occurs in rats exposed to protein deprivation in early gestation, with midgestation restoration of normal nutrition [4]. Collectively, these data suggest that an adaptive response in the placenta enhances transfer of substrates from mother to fetus, improves efficiency of substrate utilization, or both when the supply of amino acids is limited. The placenta compensates to minimize fetal growth restriction. However, placental function is not always improved with increases in weight because the histomorphology of the placenta ultimately determines placental function. Changes in Histomorphology The histomorphology and ultrastructure of the placenta change throughout normal gestation and in response to maternal nutritional manipulations [13]. In mammals, the placenta develops a large surface:volume ratio, forming highly branched structures with advancing pregnancy. Trophoblast provides the covering surface and is positioned to mediate critical steps in hormone production and immune protection of the fetus. Invasive trophoblasts also facilitate an increase in maternal vascular blood flow into the placenta [14]. In primates, the zone of exchange is represented by a single layer of syncytial trophoblast and an underlying layer of mononucleated cytotrophoblasts [15]. In rodents, this zone (labyrinth zone) is formed by a mononucleated trophoblast layer with two syncytiotrophoblast layers that serve as the structural basis of the placental barrier between the maternal-fetal blood. In ruminants, placental mononucleate trophoblasts form the majority of the interface and are primarily involved in nutrient exchange [16]. In pig, the labyrinth zone contains fetal capillaries and maternal blood sinuses and provides the means for exchange between the two circulations, as well as an interlobium that is composed of syncytiotrophoblast and maternal blood sinuses and is the site where much of the metabolic activity occurs [17]. Alterations of exchange surface area, barrier thickness, and cell composition of the different gestational ages of the placenta may all affect placental transport capacity [18]. Notably, MUN that results in human IUGR generates placentas with a reduced surface area for exchange in villi and a lowervolume density of trophoblasts [19]. These structural alterations in the placenta are mirrored in the guinea pig that is exposed to global MUN compared with control diets. The nutrient-deprived gestations exhibited placentas with surface area for exchange that were diminished by up to 70% due to reduced development of the labyrinth, while barrier thickness was increased by 40% in late gestation [20]. These histopathological changes predispose to reduced nutrient transfer to the fetus. Our work in which rats were exposed to MUN demonstrated enhanced apoptosis occurring in both the junctional and labyrinthine zones of the placenta [11]. Moreover, MUN affected to a greater degree the placenta located in the midhorn compared with proximal uterine horn positions. The marked effect of MUN on midhorn placentas may indicate a potential compounding effect of reduced

maternal vascularity, decreased oxygen supply, or other factors that are regionally distributed along the uterine horn. Reflecting the complexity of the phenotype that results from exogenous insults, these findings suggest that two insults may interact in the same animal to accentuate the morbidity associated with growth restriction. Alterations in Vasculogenesis and Angiogenesis Vasculogenesis is de novo formation of blood vessels from mesoderm precursor cells, and angiogenesis is creation of new vessels from a preexisting blood supply. Both processes are critical to the maternal-fetal exchange. Vascular endothelial growth factor (VEGF) and angiopoietin proteins [21, 22] are critical to these processes. Angiopoietin proteins contribute to the formation of mature blood vessels, but their role in MUN placentas is unknown to date. Insult induces compromise in placental vasculogenesis and angiogenesis and impairs exchange between the maternal-fetal circulations [4, 23], ultimately resulting in IUGR fetuses. For example, ewes fed with 60% global nutrient intake beginning on Day 50 of gestation had increased placental vascularity, reduced VEGF receptor expression in placentomes, and nutrient transfer deficiency [24]. The greater placentome vascularity in the feed-restricted ewes had no effect on VEGF mRNA expression, suggesting that other factors were essential in the overall process of angiogenesis; for example, the angiopoietin proteins may have a role in modulating VEGF function [25]. Endothelium-derived nitric oxide (NO) is a mediator of angiogenesis and has a role in modulating vascular resistance [26]. VEGF stimulates the release of NO and upregulates the expression of NO synthetase. A critical role for NO during human pregnancy is suggested by investigations of fetuses with IUGR [27]. The importance of NO was also demonstrated in pigs fed a protein-restricted diet for up to 60 days of gestation. The animals showed decreased placental arginine (a common substrate for NO), less NO synthesis, and reduced NO synthetase activity compared with pigs fed a normal protein diet [28]. These changes are likely one mechanism for placental vascular dysfunction that results in reduced placental-fetal growth in the protein-deficient offspring. Collectively, these results underscore that typical features of nutrient restriction models include some level of placental vascular and angiogenesis dysfunction during pregnancy. This is summarized in two studies [29, 30] of low dietary protein intake. Modifications of Nutrient Transfer Capacity Fetal nutrient availability results from several elements. These include the interrelationships of maternal food intake, availability of nutrients in the maternal circulation, and ability of the placenta to efficiently transport substrates to the fetal circulation. Global maternal nutritional status affects transporters in the placenta, thereby influencing the rate of nutrient delivery through the placenta. For example, rats fed a 50% global MUN during the last week of gestation experienced decreased glucose levels in maternal plasma [31]. The maternal-fetal glucose concentration gradient (which drives facilitative glucose diffusion across the placenta) is also reduced, and glucose transporter 3 (solute carrier family 2 [facilitated glucose transporter] member 3 [SLC2A3, previously called GLUT3]) expression is substantially decreased, suggesting a mechanism for placental glucose transport dysfunction. Although glucose

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represents the principal metabolic fuel during gestation, specific effects of maternal dietary glucose restriction on placental-fetal development have not been extensively studied to date. Placental transport of amino acids is pivotal for fetal development and is affected by the activity and location of amino acid transporter systems. In humans, reduced circulating concentrations of essential amino acids (such as leucine and lysine) are observed in growth-restricted human fetuses [32 34], implying that there is a global alteration of placental amino acid transport activity in IUGR. In animal models, rats fed a 6% casein low-protein diet from Day 5 of gestation showed 27% reduced transfer of nonmetabolizable amino acid C-a amino isobutyric acid from the maternal-fetal circulations compared with well-fed controls [35]. In addition, rats fed a 5% casein diet exhibited reduced placental system A transporter (Na -dependent neutral amino acid uptake) activity for neutral amino acids at term compared with dams pair-fed a control 20% casein diet [36]. Maternal protein restriction in rats resulted in downregulated placental nutrient transport before the onset of fetal growth restriction, suggesting that a reduced placental supply of amino acids is a causal factor for IUGR and not simply a consequence of this malady [37]. Adequate placental transport of fatty acids to the fetus is crucial for normal fetal development and growth because fatty acids have multiple roles as cell membrane components, energy sources, and precursors to cellular signaling molecules. Intrauterine growth restriction placentas showed disrupted lipid metabolism and altered microvillous plasma membrane lipid hydrolase activities; both affected the flux of essential fatty acids and preformed long-chain polyunsaturated fatty acids to the human fetus [38]. Undernourished women exhibited a relative placental deficiency of essential fatty acids, and this suggests a lower source of placental membrane fluidity and subnormal content of essential fatty acids in their offspring [39]. Placentas from pregnancies with IUGR also have decreased levels of arachidonic acid and docosahexaenoic acid [40], and fetuses affected by IUGR exhibit proportions of both these fatty acids that are lower than control proportions relative to their linoleic acid (LA) and aLA precursors [41]. Taken together, these studies demonstrate the pivotal role of fetal nutrient availability. Adequate transplacental exchange of multiple nutrients is needed to sustain normal fetal growth. A number of factors have a critical role in the regulation of placental nutrient transport to the fetus. These include NO, glucocorticoids, and imprinted genes. Nitric oxide is an angiogenic factor [42]; as such, decreased concentrations of NO synthesis can impair placental-fetal blood flow [43] to limit transfer of nutrients. For example, sheep exposed to 50% global MUN between Embryonic Day (E) 28 and E78 of gestation had levels of NO that were lower than those of controls in maternal-fetal plasma when measured at E78 [44]. Glucocorticoids affect placental expression of glucose transporters (SLC2A1 and SLC2A3) in a dose- and timedependent manner in both human [45] and rat [46] placentas. Therefore, a single injection of glucocorticoids at E16 reduced placental SLC2A1 and SLC2A3 abundance in rat and results in IUGR [45]. Long-term glucocorticoid exposure from E15 to term in the rat was also associated with IUGR, despite a doubling in placental expression of SLC2As in late gestation [46]. Concomitant downregulation of both SLC2A1 and SLC2A3 following a single injection of glucocorticoid may reflect an immediate attempt to increase fetal glucose supply to attenuate potential fetal hypoglycemia [46]. In contrast, upregulation of the SLC2As following long-term glucocorticoid exposure may be due to placental hypoxia [47] that

stimulates SLC2A expression [48]. Interestingly, fetal cortisol infusion in sheep increased placental glucose consumption and reduced placental delivery of glucose to the fetus [49]. Glucocorticoid treatment changed placental handling and fetal delivery of lactate and selected amino acids [50]. Whether or not glucocorticoids affect amino acid transporters in the placenta is still not fully known. Based on an in vitro study [51] using BeWo cells, glucocorticoids can alter placental solute carrier family 38 member 2 (SLC38A2, previously called sodium-coupled neutral amino acid transporter 2 [SNAT2]) by altering the localization of SLC38A2 and changing protein and mRNA expression. Imprinted placental genes, expressed in a manner that is parent-of-origin specific, can also regulate nutrient transport capacity of the placenta. For instance, mice exposed to restriction of dietary intake to 80% of controls from Day 3 of pregnancy showed a significant decrease in an imprinted placental Igf2 transcript [52]. Deletion of a placenta-specific transcript (P0) from the Igf2 gene, which is expressed only in the mouse labyrinthine trophoblast, decreased placental growth, limited nutrient transfer, and reduced fetal growth [53]. These data offer a mechanism by which the Igf2 gene may affect placental structure and function during maternal food restriction. It remains to be determined whether MUN, fetal nutrient demands, or other environmental signals act on the placental-specific promoter in the Igf2 gene to change its imprint status, promoter usage, or expression from the active allele. In summary, suboptimal placental growth and development following MUN yields growth-restricted fetuses. As discussed in the next section, those fetuses have altered fetal physiology in utero, resulting in newborn abnormalities with increased long-term effects well into adulthood. MUN AND FETAL DEVELOPMENT Maternal diet affects fetal growth directly by determining the amount of nutrients available, indirectly by affecting the fetal endocrine system, and epigenetically by modulating gene activity. Nutritional insults during critical periods of gestation may thereby have a permanent effect on progeny throughout postnatal life and beyond. Nutrient Levels and Fetal Growth Reduction of nutrient availability during gestation decreases fetal growth in both humans and animals [4]. MUN in pregnant women may result from low intake of dietary nutrients due to a limited supply of food or because of severe nausea and vomiting that persists long after the usual first-trimester effects [54]. Short interpregnancy intervals also result in maternal nutritional depletion at the outset of pregnancy, whereas pregnant teenage mothers compete with their own fetuses for nutrients. Infants with low birth weight babies and preterm deliveries in adolescent pregnancies were more than twice as common as in adult pregnancies, and neonatal mortality in adolescent pregnancies was almost three times higher than that for adult pregnancies [55]. In pregnant rat dams, a 5% protein reduction yielded offspring that were significantly smaller than pups born to 20% protein-fed controls [36]. Although maternal serum amino acid levels were maintained in the rat dams fed low-protein diets, fetomaternal serum amino acid ratios were reduced, suggesting diminished nutrient transfer to the fetus. Therefore, maternal protein deprivation in rats decreases the activity of Na -dependent neutral amino acid transport mediated by system A but not system alanine-serine-cysteine transporter [36]. A decrease in placental amino acid but not

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glucose transport precedes IUGR [36, 37], and this reduced amino acid supply likely contributes to the fetal growth reduction, rather than being a consequence of the disorder. Modulation of Hormone Secretion Normal pregnancy entails substantial production of hormones in the maternal, placental, and fetal compartments. Secretion of these hormones can be affected by MUN and can thereby affect fetal development. Glucocorticoids, insulin-like growth factors (IGFs), and leptin have important regulatory roles in fetal development and homeostasis. Glucocorticoids are essential for maturation of fetal tissues so that the organs they form can cope with extrauterine life [56, 57]. However, excessive exposure to endogenous glucocorticoids in utero reduced fetal growth and predisposed to anxiety disorders in adult rats [58]. Moreover, maternal global nutrient restriction during late gestation in rats induced overexposure to glucocorticoids in the fetus and disturbed the hypothalamopituitary adrenal axis in the newborn [59]. Consequently, the rat offspring has an altered set point for negative feedback, giving rise to higher basal secretion of adrenal corticosterone. The increase in basal corticosterone levels in the newborn rat accelerates the appearance of age-related neural and cognitive deficits, including atrophy of dendritic processes and cell death. Insulin-like growth factors are a family of hormones acting in autocrine, paracrine, and endocrine fashions to modulate growth [60]. The IGF ligands (IGF1 and IGF2) are regulated by a family of proteins known as the IGF-binding proteins (IGFBPs), and these interactions control fetal growth. In pregnant women, the concentration of IGFBP1 was negatively correlated with birth weight [61]. In sheep, MUN during periconceptual and gestational periods altered the IGF system to reduce fetal insulin, IGF1, and IGFBP3 levels, while enhancing IGFBP2 [62]. Alterations in the IGF cascade have a role in compromised fetal growth [62] and in fetal programming (see Note Added in Proof ). For example, a reduction in plasma IGF1 is caused by MUN in pigs, and this yielded altered proportions of muscle fibers in the offspring [63]. Conversely, in ovine gestation, an increase in IGF1 plasma concentrations was associated with increased muscle mass and myofiber hypertrophy [64]. In MUN pigs, maternal-circulating IGF2 levels were positively associated with fetal weight [65] and inversely correlated with fetal IGF2 compared with agematched controls [66], suggesting a crucial role for IGF2 in fetal growth. Taken together, these studies imply that IGFs are important for development both before and after birth. Leptin is a satiety factor that has a key role in the regulation of energy homeostasis in adults and likely has a role in fetuses as well. In humans, growth-restricted newborn plasma leptin concentrations are low; however, these concentrations increased in infants by age 1 year [67]. The enhanced plasma leptin in infants was correlated with weight gain and an increase in subcutaneous tissue [68]. Whether this increase in plasma leptin is related to changes in leptin transport, metabolism, or clearance is unknown to date. The low levels of leptin in the growth-restricted fetuses enhanced development of appetite stimulatory pathways (e.g., increased NPY mRNA expression) and suppressed development of anorexigenic inhibitory pathways [69]. Offspring born with IUGR among sheep [7073] and rodents [7476] showed resistance to the anorexigenic effects of leptin as adults, which suggests in utero programming as a source of obesity in adults. The findings among humans and in animal models indicate that undernu-

trition in utero programs leptin dysregulation to yield subsequent obesity. Collectively, these studies suggest that alteration in fetal hormones following MUN emerges as a major contributor to suboptimal fetal growth and development. Programmed changes induced by altered fetal hormone activity in utero can thus affect newborns and eventually yield disordered responses in adults. Effects of Epigenetic Influences Maternal nutrition during pregnancy can program adult disease susceptibility through epigenetic changes of the fetal genome [77] that affect the adult genotype and phenotype. The epigenetic changes result from mechanisms unrelated to the DNA sequence. Availability of amino acids and micronutrients may alter DNA methylation or modify histones. For example, a deficiency of amino acids in cultured mouse embryos resulted in reduced genomic DNA methylation and aberrant expression of the normally silent paternal H19 allele, an imprinted gene [78]. Moreover, rat dams fed a low-protein diet generally developed hypermethylation of cytosine and adenosine residues in DNA of the fetal liver [79]. However, rat dams fed low protein showed hypomethylation of the nuclear receptor peroxisome proliferator-activated receptor alpha (Ppara) and the glucocorticoid receptor (Nr3c1, previously called Gr) in the liver of their offspring [80]. These changes in the epigenetic regulation of hepatic Ppara and Nr3c1 expression may contribute to adult-onset hypertension and to impaired fat and carbohydrate metabolism. Therefore, epigenetic modifications represent a molecular mechanism by which maternal nutrition influences fetal programming, postnatal disease susceptibility, and genomic imprinting. Whether subsequent interventions can reverse in utero epigenetic effects remains to be discovered. Impact of Intrauterine Programming on Offspring Low birth weight is a major consequence of MUN in both humans and animals [81, 82]. Human newborns with low birth weight are more likely than newborns with average birth weight to develop insulin resistance, type 2 diabetes mellitus, and hypertension in adult life [2]. In addition, infants exposed to IUGR are at high risk for physical and mental impairments in later life [83]. MUN results in precocious maturation of the fetal hypothalamic pituitary axis, and these effects are associated with a delay, if not a permanent deficit, in cognitive processes [84] and school performance of affected children [85]. Adverse effects are similarly observed in undernourished newborn animals. Growth restriction in prenatally undernourished pigs was accompanied by increased adiposity of the newborn and maldevelopment of offspring skeletal muscle and liver. Moreover, IUGR newborns exhibited altered thermogenesis, glucose levels, and cholesterol homeostasis at birth, while insulin action was adversely affected later in life [86]. Rats exposed to 50% MUN in the last half of pregnancy had reduced fetal and newborn weights [11, 87, 88], with poor remodeling of vasculature, a contributing factor to subsequent hypertension [89]. The liver of IUGR rat offspring increased expression of peroxisome proliferator-activated receptor gamma coactivator 1, a regulator of mRNA expression for glucose-6-phosphatase and other gluconeogenic enzymes, suggesting that the alteration in hepatic glucose production resulted from changes in intracellular signaling. In adulthood, these rats developed obesity, with increased adipocyte differentiation, adipocyte hypertrophy, and upregulation of lipogenic genes. Moreover, the Pparg gene produces an adipogenic transcription factor that

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is significantly increased in both newborns and adults [90] and promotes adipocyte differentiation and lipid storage [91, 92]. Therefore, the abnormal activation of adipocytes in the IUGR may contribute to the development of subsequent obesity. Collectively, these studies show that suboptimal maternal nutrition not only affects fetal growth but also influences longterm outcomes of the affected offspring. SUMMARY Maternal nutrition during pregnancy is an important determinant of optimal fetal development, pregnancy outcome, and (ultimately) lifelong health as an adult. Normal placental function facilitates the maternal-fetal transfer of nutrients that are critical for the development of a healthy fetus [93]. MUN reduces fetal growth in part by impairing placental development and function. Placental alterations vary with the nutritional setting and include decreases or increases in placental weight, altered vascular development, diminished angiogenic growth factor expression, and reduced placental glucose, amino acid, and lipid transport. The plasticity of the placenta allows this pivotal tissue to respond to exogenous insults and compensate for varying nutritional status of the mother. When this response is insufficient to maintain fetal growth, IUGR results, and suboptimal outcomes may appear in newborns and persist into adult life [15]. MUN can also affect fetal growth and organ development through effects on the endocrine system or imprinted gene expression. Such effects may program future generations through epigenetic effects on the placental genome, fetal genome, or both [44]. We expect in the future to achieve new strategies to prevent and treat suboptimal fetal development as more knowledge is gained about the mechanisms regulating normal and abnormal placental function and fetal growth. NOTE ADDED IN PROOF Additional information regarding fetal programming can be found in an article by Gallaher et al., 1998 [94]. REFERENCES
1. Marsal K. Intrauterine growth restriction. Curr Opin Obstet Gynecol 2002; 14:127135. 2. Barker DJP, Clark PM. Fetal undernutrition and disease in later life. Rev Reprod 1997; 2:105112. 3. Mellor DJ. Nutritional and placental determinants of fetal growth rate in sheep and consequences for the newborn lambs. Br Vet J 1983; 139:307 310. 4. Kelly RW. Nutrition and placental development. Proc Nutr Soc Aust 1992; 17:203211. 5. Fowden AL, Giussani DA, Forhead AJ. Intrauterine programming of physiological systems: causes and consequences. Physiology 2006; 21:29 37. 6. Fowden AL, Forhead AJ, Coan PM, Burton GJ. The placenta and intrauterine programming. J Neuroendocrinol 2008; 20:439450. 7. Myatt L. Placental adaptive responses and fetal programming. J Physiol 2006; 572:2530. 8. Jansson T, Powell TL. Role of the placenta in fetal programming: underlying mechanisms and potential interventional approaches. Clin Sci 2007; 113:113. 9. Lumey LH. Compensatory placental growth after restriction of maternal nutrition in early pregnancy. Placenta 1998; 19:105111. 10. Heasman L, Clarke L, Firth K, Stephenson T, Symonds ME. Influence of restricted maternal nutrition in early to mid gestation on placental and fetal development at term in sheep. Pediatr Res 1998; 44:546551. 11. Belkacemi L, Chen CH, Ross MG, Desai M. Increased placental apoptosis in maternal food restricted gestations: role of the Fas pathway. Placenta 2009; 30:739751. 12. Langley-Evans SC, Gardner DS, Jackson AA. Association of dispropor-

13.

14.

15. 16.

17. 18. 19. 20.

21.

22.

23. 24.

25.

26. 27. 28.

29.

30.

31.

32.

33.

34.

35.

36.

37.

tionate growth of fetal rats in late gestation with raised systolic blood pressure in later life. J Reprod Fertil 1996; 106:307312. Sibley C, Turner MA, Cetin I, Ayuk P, Boyd R, DSouza SW, Glazier JD, Greenwood SL, Jansson T, Powell T. Placental phenotypes of intrauterine growth. Pediatr Res 2005; 58:827832. Wooding FBP, Flint APF. Placentation. In: Lamming GE (ed.), Marshalls Physiology of Reproduction, vol. 3, 4th ed. London: Chapman and Hall; 1994:233460. Cross JC. The genetics of pre-eclampsia: a feto-placental or maternal problem? Clin Genet 2000; 64:96103. Myers DA, Reimers TJ. Purification and endocrine evaluation of bovine binucleate and mononucleate trophoblastic cells in vitro. J Tiss Cult Meth 1998; 11:8388. Kaufmann P, Davidoff M. The guinea pig placenta. Adv Anat Embryo Cell Biol 1997; 53:191. Sibley C, Glazier J, DSouza A. Placental transporter activity and expression in relation to fetal growth. Exp Physiol 1997; 82:389402. Aherne W, Dunnill MS. Morphometry of the human placenta. Br Med Bull 1966; 22:58. Roberts CT, Sohlstrom A, Kind KL, Karl RA, Khong TY, Robinson JS, Owens PC, Owens JA. Maternal food restriction reduces the exchange surface area and increases the barrier thickness of the placenta in the guinea-pig. Placenta 2001; 22:177185. Charnock-Jones DS, Kaufmann P, Mayhew TM. Aspects of human fetoplacental vasculogenesis and angiogenesis, I: molecular regulation. Placenta 2004; 25:103113. Ferrara N, LeCouter J, Lin R, Peale F. EG-VEGF and Bv8: a novel family of tissue-restricted angiogenic factors. Biochim Biophys Acta 2004; 1654: 6978. Reynolds LP, Redmer DA. Utero-placental vascular development and placental function. J Anim Sci 1995; 73:18391851. Redmer DA, Wallace JM, Reynolds LP. Effect of nutrient intake during pregnancy on fetal and placental growth and vascular development. Domest Anim Endocrinol 2004; 27:199217. Maisonpierre PC, Suri C, Jones PF, Bartunkova S, Wiegand SJ, Radziejewski C, Compton D, McClain J, Aldrich TH, Papadopoulos N, Daly TJ, Davis S, et al. Angiopoietin-2a natural antagonist for Tie2 that disrupts in vivo angiogenesis. Science 1997; 277:5560. Ziche M, Morbidelli L. Nitric oxide and angiogenesis. J Neurooncol 2000; 50:139148. Xiao XM, Li LP. L-arginine treatment for asymmetric fetal growth restriction. J Gynecol Obstet 2005; 88:1518. Wu G, Pond WG, Flynn SP, Ott T L, Bazer FW. Maternal dietary protein deficiency decreases nitric oxide synthase and ornithine decarboxylase activities in placenta and endometrium of pigs during early gestation. J Nutr 1998; 128:23952402. Itoh S, Brawley L, Wheeler T, Anthony FW, Poston L, Hanson MA. Vasodilation to vascular endothelial growth factor in the uterine artery of the pregnant rat is blunted by low dietary protein intake. Pediatr Res 2002; 51:485491. Koumentaki A, Anthony F, Poston L, Wheeler T. Low-protein diet impairs vascular relaxation in virgin and pregnant rats. Clin Sci 2002; 102:553 560. Lesage J, Hahn D, Leonhardt M, Bondeau B, Breant B, Duprey JP. Maternal undernutrition during late gestation-induced intrauterine growth restriction in the rat is associated with impaired placental GLUT3 expression but does not correlate with endogenous corticosterone levels. J Endocrinol 2002; 174:3743. Cetin I, Marconi AM, Bozzetti P, Sereni LP, Corbetta C, Pardi G. Umbilical amino acid concentrations in appropriate and small for gestational age infants: a biochemical difference present in utero. Am J Obstet Gynecol 1988; 158:120126. Economides DL, Nicolaides KH, Gahl WA, Bernardini I, Evans MI. Plasma amino acids in appropriate- and small-for-gestational-age fetuses. Am J Obstet Gynecol 1989; 161:12191227. Cetin I, Corbetta C, Sereni LP, Marconi AM, Bozzetti P, Pardi G, Battaglia FC. Umbilical amino acid concentrations in normal and growthretarded fetuses sampled in utero by cordocentesis. Am J Obstet Gynecol 1990; 162:253261. Rosso P. Maternal-fetal exchange during protein malnutrition in rat: placental transfer of glucose and nonmetabolizable glucose analog. J Nutr 1977; 107:2000620010. Malandro MS, Beveridge MJ, Kilberg MS, Novak DA. Effect of lowprotein diet-induced intrauterine growth retardation on rat placental amino acid transport. Am J Physiol 1996; 271:C295C303. Jansson N, Pettersson J, Haafiz A, Ericsson A, Palmberg I, Tranberg M, Ganapathy V, Powell TL, Jansson T. Effect of low-protein diet-induced

Downloaded from www.biolreprod.org.

330

BELKACEMI ET AL.
intrauterine growth retardation on rat placental amino acid transport: down-regulation of placental transport of amino acids precedes the development of intrauterine growth restriction in rats fed a low protein diet. J Physiol 2006; 576:935946. Magnusson AL, Waterman IJ, Wennergren M, Jansson T, Powell TL. Triglyceride hydrolase activities and expression of fatty acid binding proteins in the human placenta in pregnancies complicated by intrauterine growth restriction and diabetes. J Clin Endocrinol Metab 2004; 89:4607 4614. Araya J, Soto C, Aguilera AM, Bosco C, Monlina R. Modification of the lipid profile of human placenta by moderate maternal undernutrition. Rev Med Chil 1995; 122:503509. Percy P, Vilbergsson G, Percy A, Mansson J, Wennergren M, Svennerholm L. The fatty acid composition of placenta in intrauterine growth retardation. Biochim Biophys Acta 1991; 1084:173177. Cetin I, Giovannini N, Alvino G, Agostoni C, Riva E, Giovannini M, Pardi G. Intrauterine growth restriction is associated with changes in polyunsaturated fatty acid fetal-maternal relationships. Pediatr Res 2002; 52:750755. Reynold LP, Killilea SD, Redmer DA. Angiogenesis in the female reproductive system. FASEB J 1992; 6:886892. Bird IM, Zhang LB, Magness RR. Possible mechanisms underlying pregnancy-induced changes in uterine artery endothelial function. Am J Physiol 2003; 284:R245R258. Wu G, Bazer FW, Cudd TA, Meininger CJ, Spencer TE. Maternal nutrition and fetal development. J Nutr 2004; 134:21692172. Hahn T, Barth S, Graf R, Engleman M, Beslapic D, Reul JM, Holsboer F, Dohr G, Desoye G. Placental glucose transporter expression is regulated by glucocorticoids. J Clin Endocrinol Metab 1999; 84:14451452. Langdown ML, Sugden MC. Enhanced placental GLUT1 and GLUT3 expression in dexamethasone-induced fetal growth retardation. Mol Cell Endocrinol 2001; 185:109117. Gude NM, Stevenson JL, Moses EK, King RG. Magnesium regulates hypoxia-stimulated apoptosis in the human placenta. Clin Sci 2000; 98: 375380. Das UG, Sadiq HF, Soares MJ, Hay WW Jr, Devaskar SU. Timedependent physiological regulation of rodent and ovine placental glucose transporter (GLUT-1) protein. Am J Physiol 1998; 274:R339R347. Baisden B, Sonne S, Joshi RM, Ganapathy V, Shkawat PS. Antenatal dexamethasone treatment leads to changes in gene expression in a murine late placenta. Placenta 2007; 28:10821090. Ward JW, Wooding FB, Fowden AL. Ovine feto-placental metabolism. J Physiol 2004; 554:529541. Jones HN, Ashworth CJ, Page KR, McArdle HJ. Cortisol stimulates system A amino acid transport and SNAT2 expression in a human placental cell line (BeWo). Am J Physiol Endocrinol Metab 2006; 291: E596E603. Coan PM, Vaughan OR, Sekita Y, Finn SL, Burton GJ, Constancia M, Fowden AL. Adaptations in placental phenotype support fetal growth during undernutrition of pregnant mice. J Physiol 2010; 588:527538. Sibley CP, Coan PM, Ferguson-Smith AC, Dean W, Hughes J, Smith P, Reik W, Burton GJ, Fowden AL, Consta ncia M, Berridge MJ. Placentalspecific insulin-like growth factor 2 (IGF-2) regulates the diffusional exchange characteristics of the mouse placenta. Proc Natl Acad Sci U S A 2004; 101:82048208. Snell LH, Haughey BP, Buck G, Marecki MA. Metabolic crisis: hyperemesis gravidarum. J Perinat Neonat Nurs 1998; 12:2637. King JC. The risk of maternal nutritional depletion and poor outcomes increases in early or closely spaced pregnancies. J Nutr 2003; 133:1732S 1736S. Snyder JM, Rodgers HF, OBrien JA, Mahli N, Magliato SA, Durham PL. Glucocorticoid effects on rabbit fetal lung maturation in vivo: an ultrastructural morphometric study. Anat Rec 1992; 232:133140. Aszterbaum M, Feingold KR, Menon GK, Williams ML. Glucocorticoids accelerate fetal maturation of the epidermal permeability barrier in the rat. J Clin Invest 1993; 91:27032708. Welberg LA, Seckl JR, Holmes MC. Inhibition of 11b-hydroxysteroid dehydrogenase, the feto-placental barrier to maternal glucocorticoids, permanently programs amygdala GR mRNA expression and anxiety-like behaviour in the offspring. Eur J Neurosci 2000; 12:10471054. Levitt NS, Lindsay SR, Holmes MC, Seckl JR. Dexamethasone in the last week of pregnancy attenuates hippocampal glucocorticoid receptor gene expression and elevates blood pressure in the adult offspring in the rat. Neuroendocrinology 1996; 64:412418. Lowe WL Jr, Kummer M, Karpen CW, Wu XD. Regulation of insulin-like growth factor I messenger ribonucleic acid levels by serum in cultured rat fibroblasts. Endocrinology 1990; 127:28542861. 61. Hills FA, English J, Chard T. Circulating levels of IGF-I and IGF-binding protein-1 throughout pregnancy: relation to birth weight and maternal weight. J Endocrinol 1996; 148:303309. 62. Osgerby JC, Wathes DC, Howard D, Gadd TS. The effect of maternal undernutrition on ovine fetal growth. J Endocrinol 2002; 173:131141. 63. Harrison AP, Tygesen MP, Sawa-Wojtanowicz B, Husted S, Tatara MR. a-Ketoglutarate treatment early in postnatal life improves bone density in lambs at slaughter. Bone 2004; 35:204220. 64. Li J, Forhead AJ, Dauncey MJ, Gilmour RS, Fowden AL. Control of growth hormone receptor and insulin-like growth factor-I expression by cortisol in ovine fetal skeletal muscle. J Physiol 2002; 541:581589. 65. Dwyer C, Strickland N. Supplementation of a restricted maternal diet with protein or carbohydrate alone prevents a reduction in fetal muscle fibre number in the guinea-pig. Br J Nutr 1994; 72:173180. 66. Roberts CT, Sohlstrom A, Kind KL, Grant PA, Earl RA, Robinson JS, Khong TY, Owens PC, Owens JA. Altered placental structure induced by maternal food restriction in guinea pigs: a role for circulating IGF-2I and IGFBP-2 in the mother? Placenta 2001; 22(suppl A):S77S82. 67. Jaquet D, Leger J, Tabone MD, Czernichow P, Levy-Marchal C. High serum leptin concentrations during catch-up growth of children born with intrauterine growth retardation. J Clin Endocrinol Metab 1999; 84:1949 1953. 68. Toprak D, Gokalp AS, Hatun S, Zengin E, Arisov AE, Yumuk Z. Serum leptin levels of premature and full-term newborns in early infancy: metabolic catch-up of premature babies. Turk J Pediatr 2004; 46:232238. 69. Bouret SG, Draper SJ, Simerly RB. Trophic action of leptin on hypothalamic neurons that regulate feeding. Science 2004; 304:108110. 70. Blache D, Celi P, Blackberrv MA, Dynes RA, Martin GB. Decrease in voluntary feed intake and pulsatile luteinizing hormone secretion after intracerebroventricular infusion of recombinant bovine leptin in mature male sheep. Reprod Fertil Dev 2000; 12:373381. 71. Morrison CD, Daniel JA, Holmberg BJ, Djiane J, Raver N, Gertler A, Keisler DH. Central infusion of leptin into well-fed and undernourished ewe lambs: effects on feed intake and serum concentrations of growth hormone and luteinizing hormone. J Endocrinol 2001; 168:317324. 72. Clarke IJ, Henry B, Iqbal J, Goding JW. Leptin and the regulation of food intake and the neuroendocrine axis in sheep. Clin Exp Pharmacol Physiol 2001; 28:106107. 73. Henry BA, Goding JW, Alexander WS, Tilbrook AJ, Canny BJ, Dunshea F, Rao A, Mansell A, Clarke IJ. Central administration of leptin to ovariectomized ewes inhibits food intake without affecting the secretion of hormones from the pituitary gland: evidence for a dissociation of effects on appetite and neuroendocrine function. Endocrinology 1999; 140:1175 1182. 74. Air EL, Benoit SC, Clegg DJ, Seeley RJ, Woods SC. Insulin and leptin combine additively to reduce food intake and body weight in rats. Endocrinology 2002; 143:24492452. 75. Shiraishi T, Oomura Y, Sasaki K, Wayner MJ. Effects of leptin and orexin-A on food intake and feeding related hypothalamic neurons. Physiol Behav 2000; 71:251261. 76. Muzzin P, Cusin I, Charnay Y, Rohner-Jeanrenaud F. Single intracerebroventricular bolus injection of a recombinant adenovirus expressing leptin results in reduction of food intake and body weight in both lean and obese Zucker fa/fa rats. Regul Pept 2000; 92:5764. 77. Gallou-Kabani C, Junien C. Nutritional epigenomics of metabolic syndrome: new perspective against the epidemic. Diabetes 2000; 54: 18991906. 78. Doherty AS, Mann MRW, Tremblay KD, Bartolomei MS, Schultz RM. Differential effects of culture on imprinted H19 expression in the preimplantation mouse embryo. Biol Reprod 2000; 62:15261535. 79. Rees WD, Hay SM, Brown DS, Antipatis C, Palmer RM. Maternal protein deficiency causes hypermethylation of DNA in the livers of rat fetuses. J Nutr 2000; 130:18211826. 80. Lillycrop KA, Phillips ES, Jackson AA, Hanson MA, Burdge GC. Dietary protein restriction of pregnant rats induces and folic acid supplementation prevents epigenetic modification of hepatic gene expression in the offspring. J Nutr 2005; 135:13821386. 81. Lechtig A, Yarbrough C, Delgado H, Habicht JP, Martorell R, Klein RE. Influence of maternal nutrition on birth weight. Am J Clin Nutr 1975; 28: 12231233. 82. Mitra K, Chowdhury MK. Maternal malnutrition, perinatal mortality and fetal pathology: a clinicopathological study. J Indian Med Assoc 2002; 100:8587. 83. Wehmer F, Hafez ES. Maternal malnutrition, low birthweight and related phenomena in man: physiological and behavioral interactions. Eur J Obstet Gynecol Reprod Biol 1975; 4:177187. 84. Bloomfield FH, Oliver MH, Hawkins P, Holloway AC, Campbell M,

38.

39.

40.

41.

42. 43.

44. 45.

Downloaded from www.biolreprod.org.

46. 47.

48.

49.

50. 51.

52.

53.

54. 55.

56.

57.

58.

59.

60.

MATERNAL UNDERNUTRITION AND PLACENTAL-FETAL DEVELOPMENT

Gluckman PD, Harding JE, Challis JRG. Periconceptional undernutrition in sheep accelerates maturation of the fetal hypothalamic-pituitary-adrenal axis in late gestation. Endocrinology 2004; 145:42784285. Granthan-McGregor S, Cheung YB, Cueto S, Glewwe P, Richter L, Strupp B. International Child Development Steering Group. Developmental potential in the first 5 years for children in developing countries. Lancet 2007; 369:6070. Kind KL, Roberts CT, Sohlstrom AI, Katsman A, Clifton PM, Robinson JS, Owens JA. Chronic maternal feed restriction impairs growth but increases adiposity of the fetal guinea pig. Am J Physiol Regul Integr Comp Physiol 2005; 288:R119R126. Desai M, Gayle D, Babu J, Ross MG. Programmed obesity in intrauterine growth-restricted newborns: modulation by newborn nutrition. Am J Physiol Regul Integr Comp Physiol 2005; 288:R91R96. Karadag A, Sakurai R, Wang Y, Guo P, Desai M, Ross MG, Torday JS, Rehan VK. Effect of maternal food restriction on fetal rat lung lipid differentiation program. Pediatr Pulmonol 2009; 44:635644. Khorram O, Momeni M, Desai M, Ross MG. Nutrient restriction in utero induces remodeling of the vascular extracellular matrix in rat offspring. Reprod Sci 2007; 14:7380.

331

85.

86.

87. 88. 89.

90. Magee TR, Han G, Cherian B, Khorram O, Ross MG, Desai M. Downregulation of transcription factor peroxisome proliferator-activated receptor in programmed hepatic lipid dysregulation and inflammation in intrauterine growth-restricted offspring. Am J Obstet Gynecol 2008; 199: 271.e1271.e5. 91. Spiegelman BM, Choy L, Hotamisligil GS, Graves RA, Tontonoz P. Regulation of adipocyte gene expression in differentiation and syndromes of obesity/diabetes. J Biol Chem 1993; 268:68236826. 92. Low JA, Handley-Derry MH, Burke SO, Peters RD, Pater EA, Killen HL, Derrick EJ. Association of intrauterine fetal growth retardation and learning deficits at age 9 to 11 years. Am J Obstet Gynecol 1992; 167: 14991505. 93. Knipp GT, Audus KL, Soares MJ. Nutrient transport across the placenta. Adv Drug Deliv Rev 1999; 38:4158. 94. Gallaher BW, Breier BH, Keven CL, Harding JE, Gluckman PD. Fetal programming of insulin-like growth factor (IGF)-I and IGF binding protein-3: evidence for an altered response to undernutrition in late gestation following exposure to periconceptual undernutrition in the sheep. J Endo 1998; 159:501508.

Downloaded from www.biolreprod.org.